Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicenter cohort study (SAM-COVID19).

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Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicenter cohort study (SAM-COVID19).

SUPPLEMENTARY MATERIAL

Supplementary Table S1. STROBE checklist.

Supplementary Table S2. Dosing details and day of the first dose of immunomodulatory drug(s) used.

Supplementary Table S3. Table S3. Demographic and clinical data of propensity score-matched patients receiving no treatment or tocilizumab (A), corticosteroids, intermediate-high dose (B), corticosteroids, puse dose (C) or combination therapy (D).

Supplementary Figure S1. Probability of remaining event- free (intubation or death) according to the different treatments used, in comparison with no treatment adjusted by the inverse probability of

treatment weight. A) Tocilizumab. B) Corticosteroids, pulse dose. Corticosteroids, intermediate-high dose and combination therapy are not included because Cox regression could not be applied.

Supplementary Figure S2. Probability of being alive according to the different treatments used, in comparison with no treatment (crude analyses). A) Tocilizumab. B) Corticosteroids, intermediate-high dose C) Corticosteroids, pulse dose. D) Combination therapy.

Supplementary Figure S3. Probability of being alive according to the different treatments used, in

comparison with no treatment adjusted by the inverse probability of treatment weight. A) Tocilizumab. B) Corticosteroids, intermediate-high dose. Corticosteroids, intermediate-high dose and combination therapy were not included as Cox regression could not be applied.

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2 Supplementary Table S1. STROBE checklist.

Item No

Recommendation Manuscript

location Title and abstract 1 (a) Indicate the study’s design with a commonly

used term in the title or the abstract

Title and abstract

(b) Provide in the abstract an informative and balanced summary of what was done and what was found

Abstract

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported

Introduction

Objectives 3 State specific objectives, including any prespecified hypotheses

Introduction, last paragraph Methods

Study design 4 Present key elements of study design early in the paper

Methods, first paragraph Setting 5 Describe the setting, locations, and relevant dates,

including periods of recruitment, exposure, follow-up, and data collection

Methods, first and second paragraphs

Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up

Methods, second paragraph

(b) For matched studies, give matching criteria and number of exposed and unexposed

Methods,

Statistical analysis Variables 7 Clearly define all outcomes, exposures,

predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable

Methods, Variables

Data sources/

measurement

8* For each variable of interest, give sources of data and details of methods of assessment

(measurement). Describe comparability of assessment methods if there is more than one group

Methods, Variables

Bias 9 Describe any efforts to address potential sources of bias

Discussion, paragraphs 2-4 Study size 10 Explain how the study size was arrived at Methods,

Statistical analysis Quantitative

variables

11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why

Methods,

Statistical analysis

Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding

Methods,

Statistical analysis

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(b) Describe any methods used to examine subgroups and interactions

Methods,

Statistical analysis (c) Explain how missing data were addressed Methods,

Variables (d) If applicable, explain how loss to follow-up

was addressed

Methods, Variables (e) Describe any sensitivity analyses Methods,

Variables and Statistical analysis Results

Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed

Results, Figure 1

(b) Give reasons for non-participation at each stage

Results, Figure 1

(c) Consider use of a flow diagram Figuren 1 Descriptive data 14* (a) Give characteristics of study participants (eg

demographic, clinical, social) and information on exposures and potential confounders

Table 1

(b) Indicate number of participants with missing data for each variable of interest

Table 1

(c) Summarise follow-up time (eg, average and total amount)

Table 2

Outcome data 15* Report numbers of outcome events or summary measures over time

Table 2

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included

Table 3, Figure 2 and Figure S1

(b) Report category boundaries when continuous variables were categorised

Table 1

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period

Not relevant

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses

Results, Table S3

Discussion

Key results 18 Summarise key results with reference to study objectives

Discussion, first paragraph

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Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential bias

Discussion, 6^th paragraph

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence

Discussion, last paragraph

Generalisability 21 Discuss the generalisability (external validity) of the study results

Discussion, last paragraph Other information

Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based

Ackowledgements

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Supplementary Table S2. Dosing details and day of the first dose of immunomodulatory drug(s) used.

Drug Variable Number of patients

Tocilizumab

Dose <400 mg 1

400 mg 10

600 mg 70

>600 mg 3

Not available 4

Number of doses 1 38

2 34

≥3 12

Not available 4

Day of first dose Day 0 43

Day 1 29

Day 2 16

Corticosteroids, intermediate- high dose

Drug used Methylprednisolone 100

Prednisone 6

Dexamethasone 2

Hydrocortisone 9

Dose (methylprednisolone or equivalent)

<40 mg/day 11

40-80 mg/day 84

81-125 mg/day 28

Day 1 35

Day 2 21

Corticosteroids, pulse dose

Drug used Methylprednisolone 56

Dexamethasone 20

Prednisone 2

Dose(methylprednisolone or equivalent)

250-499 mg/day 63

≥500 mg/day 13

Number of doses 1 7

2 5

3 32

≥4 34

Continuation with low doses 73

Day 1 28

Day 2 11

Tapering doses 73

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Table S3A.Demographic and clinical data of propensity score-matched patients receiving no treatment or tocilizumab. Data are number (proportion) of patients with known exposure to the variable except where specified.

No treatment

(n=106) Tocilizumab (n=53)

Age, median years (IQR) 68 (56-74) 68 (57-73)

Female gender 25 (23.6) 15 (28.3)

Caucasian ethnicity 94 (88.7) 48 (90.6)

Comorbidities

Cardiac disease 21 (19.8) 8 (15.1)

Hypertension 43 (40.6) 23 (43.4)

Chronic pulmonary disease 11 (10.4) 4 (7.5)

Severe chronic renal insufficiency 3 (2.8) 0

Liver cirrhosis 1 (0.9) 0

Malignancy 4 (3.7) 1 (1.9)

HIV infection 0 1 (1.9)

Obesity 10 (9.4) 5 (9.4)

Diabetes mellitus 20 (18.9) 10 (18.9)

Dementia 6 (5.7) 1 (1.9)

Admission data

Bilateral infiltrates in thorax radiography 87 (82.1) 45 (84.9)

Lymphocytes/µL, mean (SD) 1283 (1704) 1000 (876)

LDH in U/L, mean (SD) 395 (166) 382 (150)

Antiviral treatment before day 0

Lopinavir/ritonavir 80 (75.5) 46 (86.8)

Hydroxycloroquine 98 (92.5) 52 (98.1)

Remdesivir 1 (0.9) 0

Azithromycin 69 (65.1) 37 (69.8)

Data on day 0

Median days of symptoms (IQR) 8 (7-12) 10 (7-12)

Fever 53 (50) 26 (49.1)

Worsening in oxygen requirements 91 (85.8) 46 (86.8)

Ferritin >2000 ng/mL 24 (22.6) 10 (18.9)

D-dimers >1500 µg/mL 52 (49.1) 29 (54.7)

IL6 >50 pg/mL 49 (46.2) 22 (41.5)

Oxygen support at day -1

High-flow nasal cannula 4 (3.8) 2 (3.8)

Non-invasive mechanical ventilation 1 (0.9) 1 (1.9) Low molecular weight heparin

Prophylactic dose 76 (73.1) 39 (76.5)

Anticoagulant dose 11 (10.6) 7 (13.7)

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Table S3B.Demographic and clinical data of propensity score-matched patients receiving no treatment or corticosteroids, intermediate-high dose. Data are number (proportion) of patients with known exposure to the variable except where specified.

No treatment

(n=162) Corticosteroids, intermediate-

high dose (n=81)

Female gender 52 (32.0) 24 (29.6)

Caucasian ethnicity 155 (95.0) 81 (100)

Comorbidities

Hypertension 90 (55.5) 42 (51.9)

Severe chronic renal insufficiency 4 (2.4) 3 (3.7)

Liver cirrhosis 3 (1.8) 1 (1.2)

Malignancy 7 (4.3) 5 (6.1)

HIV infection 0 0

Obesity 25 (15.4) 11 (13.6)

Dementia 9 (5.5) 3 (3.7)

Admission data

LDH in U/L, mean (SD) 383 (151) 296 (161)

Azithromycin 102 (62.9) 54 (66.7)

Data on day 0

Fever 84 (51.8) 47 (58.0)

Ferritin >2000 ng/mL 43 (26.5) 25 (30.9)

D-dimers >1500 µg/mL 80 (49.2) 42 (51.9)

IL6 >50 pg/mL 54 (33.3) 27 (33.3)

Non-invasive mechanical ventilation 0 2 (2.5)

Low molecular weight heparin

Anticoagulant dose 20 (12.3) 13 (16)

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Table S3C.Demographic and clinical data of propensity score-matched patients receiving no treatment or corticosteroids, pulse dose. Data are number (proportion) of patients with known exposure to the variable except where specified.

No treatment

(n=112) Corticosteroids, pulse dose

(n=56)

Female gender 27 (24.1) 14 (25.0)

Comorbidities

Hypertension 51 (45.5) 30 (53.6)

Liver cirrhosis 2 (1.8) 1 (1.8)

Malignancy 8 (7.1) 5 (8.9)

HIV infection 0 0

Obesity 8 (7.1) 4 (7.1)

Dementia 6 (5.4) 0

Admission data

LDH in U/L, mean (SD) 401 (163) 367 (123)

Azithromycin 69 (61.6) 33 (58.9)

Data on day 0

Fever 53 (47.3) 27 (48.2)

Ferritin >2000 ng/mL 40 (35.7) 19 (33.9)

D-dimers >1500 µg/mL 58 (51.8) 29 (51.8)

IL6 >50 pg/mL 30 (26.8) 13 (23.2)

High-flow nasal cannula 1 (0.9) 0

Non-invasive mechanical ventilation 0 1 (1.8)

Low molecular weight heparin

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Table S3D.Demographic and clinical data of propensity score-matched patients receiving no treatment or combination therapy. Data are number (proportion) of patients with known exposure to the variable except where specified.

No treatment

(n=150) Combination therapy

(n=75)

Female gender 40 (26.6) 18 (24.0)

Comorbidities

Hypertension 71 (47.3) 38 (50.7)

Liver cirrhosis 0 0

Malignancy 5 (3.3) 1 (1.3)

HIV infection 0 0

Obesity 21 (14.0) 13 (17.3)

Dementia 0 0

Admission data

LDH in U/L, mean (SD) 392 (146) 382 (149)

Azithromycin 100 (66.6) 58 (77.3)

Data on day 0

Fever 80 (53.3) 38 (50.7)

Ferritin >2000 ng/mL 45 (26.6) 20 (26.7)

D-dimers >1500 µg/mL 68 (45.3) 38 (50.7)

IL6 >50 pg/mL 58 (38.6) 27 (36.0)

Non-invasive mechanical ventilation 4 (2.6) 4 (5.3) Low molecular weight heparin

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Supplementary Figure S1. Probability of remaining event- free (intubation or death) according to the different treatments used, in comparison with no treatment adjusted by the inverse probability of treatment weight. A) Tocilizumab. B) High-dose steroids. Low-dose steroids and combination therapy were not included as Cox regression could not be applied.

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Supplementary Figure S2. Probability of being alive according to the different treatments used, in comparison with no treatment (crude analyses). A) Tocilizumab.

B) Corticosteroids, intermediate-high dose. C) Corticosteroids, puse dose. D) Combination therapy.

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Supplementary Figure S3. Probability of being alive according to the different treatments used, in comparison with no treatment adjusted by the inverse probability of treatment weight. A)

Tocilizumab. B) Corticosteroids, intermediate-high dose. Corticosteroidsm pulse dose and combination therapy were not included as Cox regression could not be applied.